Myocardial contractility
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Within an [[in vivo]] intact heart, the action/response of the [[sympathetic nervous system]] is driven by precisely timed releases of a [[catecholamine]], which is a process that determines the concentration of calcium ions in the [[cytosol]] of cardiac muscle cells. The factors causing an increase in contractility work by causing an increase in intracellular calcium ions (Ca++) during contraction. {{Citation needed|date=September 2008}} |
Within an [[in vivo]] intact heart, the action/response of the [[sympathetic nervous system]] is driven by precisely timed releases of a [[catecholamine]], which is a process that determines the concentration of calcium ions in the [[cytosol]] of cardiac muscle cells. The factors causing an increase in contractility work by causing an increase in intracellular calcium ions (Ca++) during contraction. {{Citation needed|date=September 2008}} |
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==Mechanisms for altering contractility== |
== Mechanisms for altering contractility == |
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Increasing contractility is done primarily through increasing the influx of calcium or maintaining higher calcium levels in the cytosol of cardiac myocytes during an [[Cardiac action potential|action potential]]. This is done by a number of mechanisms:{{cn|date=March 2021}} |
Increasing contractility is done primarily through increasing the influx of calcium or maintaining higher calcium levels in the cytosol of cardiac myocytes during an [[Cardiac action potential|action potential]]. This is done by a number of mechanisms:{{cn|date=March 2021}} |
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# Sympathetic activation. Increased circulating levels of catecholamines (which can bind to [[Adrenergic receptor|β-Adrenergic]] activation) as well as stimulation by sympathetic nerves (which can release [[Norepinephrine|norepinepherine]] that binds to [[Beta-1 adrenergic receptor|β1-adrenoceptors]] on myocytes) causes the [[Gs subunit|Gs subunit]] of the receptor to render [[Adenylyl cyclase|adenylate cyclase]] activated, resulting in increase of [[CAMP-dependent pathway|cAMP]] - which has a number of effects including [[Phosphorylation|phosphorylating]] phospholamban (via [[Protein kinase A]]). |
# Sympathetic activation. Increased circulating levels of catecholamines (which can bind to [[Adrenergic receptor|β-Adrenergic]] activation) as well as stimulation by sympathetic nerves (which can release [[Norepinephrine|norepinepherine]] that binds to [[Beta-1 adrenergic receptor|β1-adrenoceptors]] on myocytes) causes the [[Gs subunit|Gs subunit]] of the receptor to render [[Adenylyl cyclase|adenylate cyclase]] activated, resulting in increase of [[CAMP-dependent pathway|cAMP]] - which has a number of effects including [[Phosphorylation|phosphorylating]] phospholamban (via [[Protein kinase A]]). |
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# Phosphorylating [[phospholamban]]. When phospholamban is not phosphorylated, it inhibits the [[ |
# Phosphorylating [[phospholamban]]. When phospholamban is not phosphorylated, it inhibits the [[calcium pump]]s that pump calcium back into the [[sarcoplasmic reticulum]]. When it's phosphorylated by PKA, levels of calcium stored in the sarcoplasmic reticulum are increased, allowing a higher rate of calcium being released at the next contraction. However, the increased rate of calcium sequestration also leads to an increase in [[lusitropy]]. |
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# Sensitizing [[Troponin C|troponin-C]] to the effects of calcium. |
# Sensitizing [[Troponin C|troponin-C]] to the effects of calcium. |
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# Phosphorylating [[L-type calcium channels]]. This will increase their [[Permeability (Earth sciences)|permeability]] to calcium, allowing more calcium into the myocyte cells, increasing contractility. |
# Phosphorylating [[L-type calcium channels]]. This will increase their [[Permeability (Earth sciences)|permeability]] to calcium, allowing more calcium into the myocyte cells, increasing contractility. |
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# An abrupt increase in [[afterload]] enhances myocardial contractility and prolongs systolic ejection time through the [[Anrep effect]]. This response involves a two-phase recruitment of myosin from resting states to contraction-ready configurations, boosting the heart's contractile force.{{Cite journal |last1=Reil |first1=Jan-Christian |last2=Reil |first2=Gert-Hinrich |last3=Kovács |first3=Árpád |last4=Sequeira |first4=Vasco |last5=Waddingham |first5=Mark T. |last6=Lodi |first6=Maria |last7=Herwig |first7=Melissa |last8=Ghaderi |first8=Shahrooz |last9=Kreusser |first9=Michael M. |last10=Papp |first10=Zoltán |last11=Voigt |first11=Niels |last12=Dobrev |first12=Dobromir |last13=Meyhöfer |first13=Svenja |last14=Langer |first14=Harald F. |last15=Maier |first15=Lars S. |date=August 2020 |title=CaMKII activity contributes to homeometric autoregulation of the heart: A novel mechanism for the Anrep effect |journal=The Journal of Physiology |language=en |volume=598 |issue=15 |pages=3129–3153 |doi=10.1113/JP279607 |issn=0022-3751 |pmc=7657994 |pmid=32394454}}{{Cite journal |last1=Sequeira |first1=Vasco |last2=Maack |first2=Christoph |last3=Reil |first3=Gert-Hinrich |last4=Reil |first4=Jan-Christian |date=2024-01-05 |title=Exploring the Connection Between Relaxed Myosin States and the Anrep Effect |url=https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.123.323173 |journal=Circulation Research |language=en |volume=134 |issue=1 |pages=117–134 |doi=10.1161/CIRCRESAHA.123.323173 |pmid=38175910 |issn=0009-7330|url-access=subscription }} |
# An abrupt increase in [[afterload]] enhances myocardial contractility and prolongs systolic ejection time through the [[Anrep effect]]. This response involves a two-phase recruitment of myosin from resting states to contraction-ready configurations, boosting the heart's contractile force.{{Cite journal |last1=Reil |first1=Jan-Christian |last2=Reil |first2=Gert-Hinrich |last3=Kovács |first3=Árpád |last4=Sequeira |first4=Vasco |last5=Waddingham |first5=Mark T. |last6=Lodi |first6=Maria |last7=Herwig |first7=Melissa |last8=Ghaderi |first8=Shahrooz |last9=Kreusser |first9=Michael M. |last10=Papp |first10=Zoltán |last11=Voigt |first11=Niels |last12=Dobrev |first12=Dobromir |last13=Meyhöfer |first13=Svenja |last14=Langer |first14=Harald F. |last15=Maier |first15=Lars S. |date=August 2020 |title=CaMKII activity contributes to homeometric autoregulation of the heart: A novel mechanism for the Anrep effect |journal=The Journal of Physiology |language=en |volume=598 |issue=15 |pages=3129–3153 |doi=10.1113/JP279607 |issn=0022-3751 |pmc=7657994 |pmid=32394454}}{{Cite journal |last1=Sequeira |first1=Vasco |last2=Maack |first2=Christoph |last3=Reil |first3=Gert-Hinrich |last4=Reil |first4=Jan-Christian |date=2024-01-05 |title=Exploring the Connection Between Relaxed Myosin States and the Anrep Effect |url=https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.123.323173 |journal=Circulation Research |language=en |volume=134 |issue=1 |pages=117–134 |doi=10.1161/CIRCRESAHA.123.323173 |pmid=38175910 |issn=0009-7330|url-access=subscription }} |
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# An increase in heart rate also stimulates inotropy ([[Bowditch effect]]; treppe; frequency-dependent inotropy). This is probably due to the inability of Na+/K+-[[ATPase]] to keep up with the sodium influx at the higher frequency of action potentials at elevated heart rates |
# An increase in heart rate also stimulates inotropy ([[Bowditch effect]]; treppe; frequency-dependent inotropy). This is probably due to the inability of Na+/K+-[[ATPase]] to keep up with the sodium influx at the higher frequency of action potentials at elevated heart rates{{cite book|title=Cardiovascular Physiology Concepts|author=Richard Klabunde|date=3 November 2011|publisher=Lippincott Williams & Wilkins |isbn=978-1451113846}} |
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# Drugs. Drugs like [[digitalis]] can act as a positive inotropic agent by inhibiting the Na+/K+ pump. High Na+ concentration gradient is necessary to pump out sarcoplasmic calcium via the Na+/Ca++ [[antiporter]]. Inhibition of the Na+/K+ causes extra sodium to accumulate inside the cell. The buildup the Na+ concentration inside the cell will cause the gradient from inside the cell to the outside of the cell to decrease slightly. This action will make it more difficult for calcium to leave the cell via the Na+/Ca++ antiporter. |
# Drugs. Drugs like [[digitalis]] can act as a positive inotropic agent by inhibiting the Na+/K+ pump. High Na+ concentration gradient is necessary to pump out sarcoplasmic calcium via the Na+/Ca++ [[antiporter]]. Inhibition of the Na+/K+ causes extra sodium to accumulate inside the cell. The buildup the Na+ concentration inside the cell will cause the gradient from inside the cell to the outside of the cell to decrease slightly. This action will make it more difficult for calcium to leave the cell via the Na+/Ca++ antiporter. |
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# Increase the amount of calcium in the sarcoplasm. More calcium available for [[Troponin]] to use will increase the force developed. |
# Increase the amount of calcium in the sarcoplasm. More calcium available for [[Troponin]] to use will increase the force developed. |
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